Catalyst – solid sorbent – or support therefor: product or process – Catalyst or precursor therefor – Organic compound containing
Reexamination Certificate
1998-05-01
2003-02-18
Wood, Elizabeth D. (Department: 1755)
Catalyst, solid sorbent, or support therefor: product or process
Catalyst or precursor therefor
Organic compound containing
C502S163000, C502S167000, C502S168000, C502S171000
Reexamination Certificate
active
06521561
ABSTRACT:
BACKGROUND OF THE INVENTION
The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages (reviewed in, e.g., Stinson, S. C.,
Chem Eng News
, Sep. 28. 1992, pp. 46-79) include fewer side effects and greater potency of enantiomerically pure compounds.
Traditional methods of organic synthesis have often been optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: the use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”); or the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates often requires the use of resolving agents; this process may be inconvenient and is certain to be time-consuming. Furthermore, resolution often means that the undesired enantiomer is discarded, thereby wasting half of the material.
SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a process for enantioselective chemical synthesis which generally comprises the addition of a nucleophile to a &pgr;-bond in the presence of a non-racemic chiral catalyst to produce a enantiomerically enriched product. The &pgr;-bond containing substrate comprises a carbon-carbon or carbon-heteroatom &pgr;-bond, the nucleophile is typically the conjugate base of a weak acid, and the chiral catalyst comprises an asymmetric tetradentate or tridentate ligand complexed with a main-group metal ion. In the instance of the tetradentate ligand, the catalyst complex has a rectangular planar or rectangular pyramidal geometry. The tridentate ligand-metal complex assumes a planar or trigonal pyramidal geometry. In preferred embodiment, the ligand has at least one Schiff base nitrogen complexed with the metal at the core of the catalyst. In another preferred embodiment, the ligand provides at least one stereogenic center within two bonds of a ligand atom which coordinates the metal.
In general, the metal atom is a main-group metal from Groups 1, 2, 12, 13, or 14 and may be in its highest state of oxidation. In preferred embodiments, the metal atom is selected from the group comprising Li, Be, Na, Mg, K, Ca, B, Al, Ga, In, Zn, Cd, Hg, Si, Ge, and Sn. In highly preferred embodiments, the metal is Al.
Exemplary substrates for the subject asymmetric nucleophilic addition reaction include aldehydes, enals, ketones, enones, enoates, &agr;,&bgr;-unsaturated imides, imines, oximes, and hydrazones.
In preferred embodiments, the subject transformation can be represented by the conversion of 1 to 2, wherein the asterisk in 2 indicates an asymmetric center.
wherein
R, R′, and R″ represent, independently for each occurrence, hydrogen, alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH
2
)
m
—R
80
;
X is selected from the group comprising CR
2
, O, S, Se, and NR″;
Y is selected, independently for each occurrence, from the set comprising H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, SiR
3
and SnR
3
; and
Nu is selected from the set comprising conjugate bases of weak Bronsted acids—e.g. cyanide, azide, isocyanate, thiocyanate, alkoxide, thioalkoxide, carboxylate, thiocarboxylate—and carbanions;
R
80
represents and unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle; and
m is an integer in the range 0 to 8 inclusive.
In a preferred embodiment, the method includes combining a substrate that comprises a reactive &pgr;-bond, a nucleophile, and a non-racemic chiral catalyst as described herein, and maintaining the combination under conditions appropriate for the chiral catalyst to catalyze a stereoselective addition of the nucleophile to a reactive &pgr;-bond of the substrate.
In preferred embodiments, the chiral catalyst which is employed in the subject reaction is represented by the general formula:
in which
Z
1
, Z
2
, Z
3
and Z
4
each represent a Lewis base;
the C
1
moiety, taken with Z
1
, Z
3
and M, and the C
2
moiety, taken with Z
2
, Z
4
and M, each, independently, form a heterocycle;
R
1
, R
2
, R′
1
and R′
2
each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached,
R
40
and R
41
each independently are absent, or represent one or more covalent substitutions of C
1
and C
2
with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached,
or any two or more of the R
1
, R
2
, R′
1
, R′
2
R
40
and R
41
taken together form a bridging substituent;
with the proviso that C
1
is substituted at least one site by R
1
, R′
1
or R
41
, and C
2
is substituted at least one site by R
2
, R′
2
or R
40
, and at least one of R
1
, R′
1
, and R
41
is taken together with at least one of R
2
, R′
2
and R
40
to form a bridging substituent so as to provide Z
1
, Z
2
, Z
3
and Z
4
as a tetradentate;
M represents the main-group metal ion; and
A represents a counterion or a nucleophile,
wherein each R
1
, R
2
, R′
1
, R′
2
R
40
and R
41
are selected to provide at least one stereogenic center in the tetradentate ligand.
In exemplary embodiments, R
1
, R
2
, R′
1
and R′
2
, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH
2
)
m
—R
8
;
each R
40
and R
41
occuring in 100 independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH
2
)
m
—R
8
;
R
8
represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
Z
1
, Z
2
, Z
3
and Z
4
are independently selected from the group consisting of nitrogen, oxygen, phosphorus, arsenic, and sulfur; and
m is zero or an integer in the range of 1 to 8.
For example, the catalyst can be represented by the general formula:
in which
the substituents R
1
, R
2
, Y
1
, Y
2
, X
1
, X
2
, X
3
and X
4
each, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH
2
)
m
—R
8
,
or any two or more of the substituents taken together form a carbocyle or heterocycle ring having from 4 to 8 atoms in the ring structure,
with the proviso that at least one of R
1
, Y
1
, X
1
and X
2
is covalently bonded to at least one of R
2
, Y
2
, X
3
and X
4
to provide the &bgr;-iminocarbonyls to which they are attached as a tetradentate ligand, and at least one of Y
1
and Y
2
is a hydrogen;
R
8
represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle , or a polycycle;
m is zero or an integer in the range of 1 to 8;
M represents the main-group metal; and
A represents a counterion or
Jacobsen Eric N.
Sigman Matthew S.
Foley & Hoag LLP
Gordon Dana M.
President and Fellows of Harvard College
Wood Elizabeth D.
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